As the human HLA-D genetic region is structurally analogous to the murine H2-I region, it should also control human immune responses using T-lymphocyte clones which recognize cell-surface antigens encoded by the D-region and influenza virus-specific clones which express antigen-specific help and are restricted to D-region interaction products. The genetic restriction of helper clones will be identified in panel studies using HLA phenotyped, histocompatible and histoincompatible antigen presenting cells in population and family studies. Restriction specificities will be further correlated with subregions of HLA-D as detected by exquisitely specific alloreactive T.Cs defining new D-region epitopes and gene products. The ability of cones to mediate help will be assayed using an ELISA to detect induction of in vitro production of specific antibodies to influenza virus. Murine monoclonal antibodies directed against human Class II antigens will also be used to block presentation in analyses to identify functionally important interaction molecules. With the above approaches it should be possible to begin to identify the specific genetic regions which control human immune responsiveness. If the clinical manipulation of immunity is ever to be realized in humans, then it must be grounded in a firm structural and functional understanding of the human HLA-D region. Through the use of functional, antigen-specific T-cell clones it should be possible to elucidate how human immune networks operate. The proposed studies are, therefore, prerequisition steps toward the clinical use of immunomodulatory therapy.